Nu-oxides of pyridyl ketone omicron-hydrocarbonoximes



United States Patent 3,205,234 N-OXIDES 0F PYRIDYL KETONE O-HYDROCARBONOXIMES Edward L. Schumann, Portage Township, Kalamazoo County, Mich.,assignor to The Upjohn Company, Kalamazoo, Mich, a corporation of Delaware No Drawing. Filed June 30, 1961, Ser. No. 120,939

2 Claims. (Cl. 260-296) This invention pertains to novel chemical compounds, novel pharmaceutical compositions containing the same, and a novel process. More particularly, the invention is directed to N-oxides of pyridyl ketone O-hydrocarbonoximes, oral and parenteralpharmaceutical compositions containing the same, and to a process for controlling neuromuscular and neurotic reactions in mammals.

The novel N-oxides of pyridyl ketone O-hydrocarbonoximes of the invention comprise compounds represented by the structural formula:

wherein R is selected from the group consisting of hydrogen atoms and alkyl groups of from l-to 6 atoms, inclusive, for example, methyl, ethyl, propyl, butyl, amyl, hexyl, and isomeric forms thereof; R is selected from the group consisting of alkyl of from 1 to 6 carbon atoms as above, phenyl, and alkylphenyl of from 7 to 9 carbon atoms, inclusive, for example, tolyl, xylyl, and mesityl; and R is hydrocarbon of from one to twelve carbon atoms, inclusive. The term hydrocarbon of from one to twelve carbon atoms, inclusive, includes (a) saturated and unsaturated acyclic aliphatic hydrocarbon such as alkyl of which examples are methyl, ethyl, propyl, butyl, amyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, and isomeric forms thereof; alkenyl of which examples are allyl, butenyl, pentenyl, hexenyl, heptenyl, and octenyl; and alkynyl of which examples are propargyl, butynyl, hexynyl, and octynyl; (b) saturated and unsaturated cycloaliphatic hydrocarbon of which examples are cyclopropyl, cyclobutyl, cyclopentyl, 2-cyclopentenyl, l-cyclopentenyl, cyclohexyl, 2cyclohexenyl, cycloheptyl, and cyclooctyl; (c) saturated and unsaturated cycloaliphaticalkyl hydrocarbon of which examples are cyclopentylmethyl, 2-cyclopentenylmethyl, cyclohexylmethyl, 2-cyclohexenylmethyl, and cyclohexylethyl; and (d) saturated and unsaturated araliphatic hydrocarbon of which examples are benzyl, Z-phenethyl, cinnamyl, 1- naphthylmethyl, and Z-naphthylmethyl; and the like.

The invention also includes the acid addition salts of compounds of the above structural formula with acids such as hydrochloric acid, hydrobromic acid, nitric acid,

phosphoric acid, sulfuric acid, methanesulfonic acid, ptoluenesulfonic acid, and the like.

An object of this invention is to provide new and useful chemical compounds. Another object of the invention is to provide compounds represented by Formula I, above. Still another object of the invention is to provide N-oxides of pyridyl ketone O-hydrocarbonoximes, including their acid addition salts, which are safe and effective pharm-acologics. A further object of the invention is to provide pharmaceutical compositions containing as the essential active ingredient thereof the compounds of Formula I, above, including their acid addi tions salts. A still further object of the invention is to provide a process for controlling neuromuscular, neurotic, psychotic, and psychoneurotic conditions in mamketoxime by an analogous procedure.

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mals. Other objects of the invention will be apparent to those skilled in the art.

These and other objects of the inveention are accomplished since it has now been found that the N-oxides of pyridyl ketone O-hydrocarbonoximes of this invention (compounds having Formula I, above) possess unexpected and valuable pharmacologic activities. The compounds are active and useful as anti-inflammatory agents, analgetics, anticonvulsants, muscle relaxants, tranquilizers, antipyretic agents, and drug potentiators (e.g., p0- tentiation of barbiturate-induced sleep in mammals).

The novel compounds of the invention having Formula I, above, are prepared by reacting a pyridyl ketone O-hydrocarbonoxime represented by the structural formula:

R1 R :NORz

ventional procedures such as solvent evaporation, solvent extraction, vacuum distillation, and recrystallization. These N-oxides readily form salts with acids, and the salts can be prepared in a convenient manner by neutralization of the N-oxides with an equivalent of the desired acid, or if desired, by metathesis.

The pyridyl ketone O-hydrocarbonoximes of Formula II can be prepared by etherificati-on of pyridyl ketoximes of the structural formula:

N III wherein R and R are as defined above. General methods for the preparation of pyridyl ketoximes of Formula III are known, and the particular preparation of certain pyridyl ketoximes has been reported previously. Engler et a1. (Ber. 24, 2528, 1891) described the preparation of 2-pyridyl methyl ketoxime by reaction of '2-pyridyl methyl ketone with hydroxylamine hydrochloride in an aqueous sodium hydroxide medium. Engler et .al. (Ber. 22, 598, 1889) prepared 3-pyridyl methyl Similarly, Pinner (Ber. 34, 4251, 1901) prepared 4-pyridyl methyl ketoxime from 4-pyridyl methyl ketone. Using the methods described above or other conventional methods for the preparation of oximes, other pyridyl ketoximes of Formula III can be prepared from the corresponding pyridyl ketones. For example, 2-pyridyl ethyl ketone, 6-methyl- Z-pyridyl methyl ketone, 2-pyridyl n-pr-opyl ketone, 5-cthyl-2-pyridyl methyl ketone, 5-methyl-2-pyridyl methyl ketone, 4,6-dimethyl-2-pyridyl methyl ketone, 2-pyridyl isopropyl ketone, Z-pyridyl tert.butyl ketone, 2-pyridyl n-hexyl ketone, Z-pyridyl n-butyl ketone, 2-pyridyl sec.butyl ketone, Z-pyridyl isobutyl ketone, 2-pyridyl l-methylbutyl ketone, S-ethyl-Z-pyridyl n-pro- .pyl ketone, 4,5-diethyl-2-pyridyl n-propyl ketone, 4-et-hyl- 2-pyridyl methyl ketone, S-n-butyl-Z-pyridyl ethyl ketone, 6-ethyl-2-pyridyl methyl ketone, S-n-butyl-Z-pyridyl n-propyl ketone, 5-methyl-2-pyridyl n-propyl ketone, 3-pyridyl ethyl ketone, 6-methyl-3-pyridyl methyl ketone, 4-methketone,

yl-3-pyridyl methyl ketone, 3-pyridyl n-propyl ketone, 6-ethyl-3pyridyl ethyl ketone, 6-n-propyl-3-pyridyl n-propyl ketone, 2-isobutyl-5-isopropyl-3-pyridyl methyl ketone, 2-methyl-3-pyridyl methyl ketone, 2,6-dimethyl- 3-pyridyl methyl ketone, 2,4,6-trimethyl-3-pyridyl methyl ketone, 2,5-dimethyl-6-ethyl-3-pyridyl methyl ketone, 6-n-amyl-3-pyridyl n-amyl ketone, 3-pyridyl n-hexyl ketone, 6-methyl-3-pyridyl n-propyl ketone, 4-n-propyl- 3-pyridyl n-propyl ketone, 2,4-dimethyl-3-pyridyl methyl 3-pyridyl n-butyl ketone, 6-methyl-3-pyridyl ethyl ketone, 6-methyl-3-pyridyl n-bu-tyl ketone, 6-methyl-3-pyridyl n-amyl ketone, -ethyl-3-pyridyl methyl ketone, 4-pyridyl n-propyl ketone, 4-pyridyl n-butyl ketone, 5-ethyl-2-methyl-4-pyridyl methyl ketone, Z-methyl-4-pyridyl n-propyl ketone, 2-methyl-4-pyridyl n-butyl ketone, 4-pyri-dyl ethyl ketone, 2-pyridyl phenyl ketone, 4-methyl-2-pyridyl phenyl ketone, 2-pyridyl o-tolyl ketone, 3-pyridyl phenyl ketone, 2-methyl-3-pyridyl phenyl ketone, 3-pyridyl m-tolyl ketone, S-pyridyl p-tolyl ketone, 3-pyr-idyl mesityl ketone, 4-pyridyl phenyl ketone, and 2,6-dimethyl-4-pyridyl phenyl ketone, can be converted to the corresponding pyridyl ketoximes in this manner.

The etherific-ation of the pyridyl ketoximes can be effected by reaction, in the presence of a base, of a compound according to Formula III with a compound of the structural formula R X wherein R is hydrocarbon of from one to twelve carbon atoms, inclusive, as hereinbefore defined; and X represents a halogen atom, e.g., chlorine, bromine, or iodine. Generally speaking, the preferred base employed in the etherification is sodium methoxide. Bases such as sodium ethoxide and like alkoXides, sodium hydroxide, potassium carbonate, etc., can also be employed. The reaction is normally carried out in a solvent in which the reactants, but not necessarily the base, are soluble. Methanol is the preferred solvent but solvents such as acetone, ethanol, Z-butanone, propanol, and higher alkanols can also be employed. The reaction is advantageously carried out at elevated temperature and preferably under conditions of reflux. The desired product can be isolated from the react-ion mixture in .a convenient manner by addition of water follower by solvent extraction of the oil which separates.

The N-oxides of pyridyl ketone O-hydrocarbonoximes are also readily prepared by reacting an N-oxide of pyridyl ketone represented by the structural formula:

wherein R and R are as defined above, with an O-substituted hydroxylamine in an inert organic solvent, illus- .tratively, ethanol, methanol, and the like. The N-oxides of pyridyl ketone O-hydrocarbonoximes thus obtained are separated from the reaction mixture and recovered in pure form by conventional procedures such as solvent evaporation, solvent extraction, vacuum distillation, and recrystallization.

When used in therapy, the novel N-oxides of pyridyl ketone O hydrocarbonoximes in the form of the free base or in the form of acid addition salts with pharmacologically acceptable acids, can be formulated in novel unit dosage compositions for administration via oral or parenteral routes.

As employed herein, unit dosage means that quantity or amount of a composition which is physically separable and contains a readily determinable quantity of active ingredient. Theproportion of active ingredient in a unit dosage is determined by (a) the individual characteristics of the active ingredients and the carrier and (b) the therapeutic effect desired. Representative unit dosages are, e.g., a tablet, a capsule, a pill, a pow- 'N-acetyl-p-aminophenol,

der packet, a wafer, a cachet, a teasponful, a tablespoonful, a drop, a cubic centimeter, and segregated multiples thereof.

Unit dosage compositions for oral administration can be formulated with a pharmaceutical carrier in solid or liquid forms. Suitable solid forms include, for example, tablets, pills, capsules, granules, powders, wafers, and cachet's. Advantageously, the pharmaceutical carrier for such solid forms includes cornstarch, lactose, dicalcium phosphate, terra alba (calcium sulfate), talc, stearic acid, magnesium stearate, gums, and functionally similar materials. The tablets or pills can be laminated or otherwise compounded to provide unit dosages affording the advantage of prolonged or delayed action or of predetermined sequential release of the medication. For example, the tablet or pill can be compounded having concentric laminae. The laminae are separated by enteric coating, for example, one which resists disintegration in the stomach, or otherwise permits the inner laminae to pass intact through the stomach into the duodenum for release there or further in the intestines. A variety of substances can be used for such enteric layers or coatings; representative ones include a number of polymeric acids or mixtures of polymeric acids with such materials as shellac, shellac and cetyl alcohol, cellulose acetate phthalate, and the like. A particularly advantageous enteric coating comprises a styrene-maleic acid copolymer.

Suitable liquids forms include solutions, suspensions, and emulisons. Advantageously, the pharmaceutical carrier for such liquid forms comprises water, oils, water-oil emulsions, and the like. If desired, suitable dispersing or suspending agents can be included, for example, tragacanth, acacia, alginates, dextran, sodium carboxymethylcellulose, methylcellulose, polyvinylpy-rrolidone, gelatin, and mixtures thereof. Oils suitable for solutions and water-oil emulsions include cottonseed oil, sesame oil, coconut oil, and peanut oil. Liquid compositions can contain from about 1% to about 50%, weight by volume, of the active ingredient.

For parenteral administration the N-oxides of pyridyl ketone O-hydrocarbonoximes can be formulated in dilute, sterile aqueous solutions, aqueous suspensions, and oil solutions or suspensions, for intramuscular or intraperitoneal injections, or like routes.

The dosage of N-oxide of pyridyl ketone O-hydrocarbonoxime depends upon the route of administration, and the circumstances of treatment (e.g., severity of the condition to be treated and the duration of treatment), as well as the patients age, weight, and general physical condition. In general, a total daily dosage of from about 1 to about 50 mg./kg. of body weight is effective. Single daily, divided daily, or intermittent schedules can be employed.

For example, the novel compounds of this invention can be administered to adults in single doses of from about 25 to about 500 mg. given 1 to 4 times daily to a total daily dose of from about 25 to about 2000 mg. Single oral doses of 5 ml. (1 teaspoonful) containing from about 1% to about 20% active ingredient are preferred for liquid preparations.

Where a combination of pharmacologic effects is desired, compositions containing, in addition to the aforesaid principal active ingredients, one or more of the following secondary active ingredients can be employed advantageously; additional tranquilizers such as reserpine, chlorpromaz-ine, meprobamate, and ectylurea; sychic energizers such as methylphenidate hydrochloride and a-ethyltryptamine acetate; sedatives such as glutethimide, petrichloral, chloral hydrate, and methyprylon; hypotensive agents such as phenoxybenzamine hydrochloride; analgesics such as aspirin, phenacetin, salicylamide, and codeine; antispasrnodics such as methscopolamine bromide and propantheline bromide; anticonvulsants such as diphenylhydantoin, paramethadione, phenylacetylurea, and phensuxamide;

anti-arthritic agents such as prednisolone, methylprednisolone, and wfluoroprednisolone; and muscle relaxants such as chlorzoxazone, carisoprodol, and phenaglycodol. The amounts of the foregoing secondary active ingredients to be incorporated in the present compositions should not exceed the amounts comprising individual doses of the said secondary active ingredients where they are employed singly.

The N-oxides of pyridyl ketone O-hydrocarbonoximes of this invention are of further interest, because they protect mammals, e.g., mice, rats, cats, guinea pigs, and rabbits from convulsions and death due to thiosemicarbazide (TSC) toxicity. In this respect, the new compounds are substantially equivalent to the best tranquilizers now known in protecting mammals from toxicity and the pyridoxal (vitamin B depletion caused by TSC. Furthermore, the compounds of the invention are useful for investigating the biochemical mechanism of thiosemicarbazide toxicity and the biochemical functions of vitamin B The following examples are illustrative of the process and products of the present invention, but are not to be construed as limiting.

Example 1.Preparatin of the N-oxide 0f 4-pyridyl methyl ketone O-n-propyloxime Part A: Preparation of 4-pyria'yl methyl ketone O-npr0pyloxime.A solution of 2.5 g. (0.11 mole) of metallic sodium in 110 ml. of methanol was cooled in an ice bath, and 15 g. (0.11 mole) of 4-pyridyl methyl ketoxime was added. The solution was then warmed to about 25 C., and 13.5 g. (0.11 mole) of n-propyl bromide was added over an interval of minutes. After heating under reflux for 1 hr., the reaction mixture was cooled in an ice bath and poured into 500 ml. of ice-water. The ice-water mixture was extracted with two 250-ml. portions of ether. The ether extracts were combined, washed with 500 ml. of water, and dried over anhydrous potassium carbonate. The ether was removed and the residue was distilled to give 7.5 g. of 4-pyridyl methyl ketone O-n-propyloxime boiling at 58 to 60 C. at 0.025 mm. of mercury pressure, and having a refractive index, n of 1.5178.

Analysis.-Calcd for C H N O: C, 67.38; H, 7.92; N, 15.72. Found: C, 67.24; H, 7.86; N, 15.80.

Part B: Preparation of the N-oxide of 4-pyria'yl methyl ketone O-n-propyloxime-To a solution of g. (0.084 mole) of 4-pyridyl methyl ketone O-n-propyloxime (prepared as in Part A, above) in 80 ml. of glacial acetic acid was added 13.5 ml. of 30% hydrogen peroxide. This reaction mixture Was heated at 70 C., with stirring, overnight. The solvent was evaporated on a steam bath under reduced pressure, and the residue thus obtained was mixed with 50 ml. of water. The water was evaporated under reduced pressure to give a semi-solid gum. The gum was dissolved in a small amount of ethyl acetate and technical hexane (essentially a mixture of methyl-substituted pentanes and n-hexane having a boiling range of 140 to 160 F.) was added to cloudiness. There was thus obtained 6 g. of crystals melting at 104 to 109 C. After recrystallization from technical hexane, 4.5 g. of N-oxide of 4-pyridyl methyl ketone O-n-propyloxime having a melting point of 108 to 112 C. was obtained.

Analysis.Calcd for G i-1 N 0 C, 61.83; H, 7.26; N, 14.43. Found: C, 61.55; H, 7.23; N, 14.45.

Example 2.Preparation' of the N-oxide of 4-pyridyl methyl ketone O-methyloxime To a solution of 6.9 g. (0.05 mole) of the N-oxide of 4-pyridyl methyl ketone in 100 ml. of 95% ethanol was added a solution of 6.3 g. (0.075 mole) of methoxyamine hydrochloride in 50 ml. of water, and a solution of 8.2 g. (0.1 mole) of sodium acetate in 50 ml. of water. The reaction mixture was heated on a steam bath for about 30 min., and stored overnight at about 4 C. After re- Example 3.Preparati0n of the N-oxide of 4-pyridyl phenyl ketone O-n-propyloxime and the hydrochloride thereof A solution of 19.9 g. (0.1 mole) of the N-oxide of 4- pyridyl phenyl ketone in 250 ml. of ethanol was mixed with a solution of 13.4 g. (0.12 mole) of O-n-propylhydroxylamine hydrchloride in 50 ml. of water, and a solution of 11.5 g. (0.14 mole) of sodium acetate in 30 ml. of water. The mixture was heated on a steam bath for about 30 minutes, and was then cooled to about 25 C. with stirring. The solvent was then removed under reduced pressure, and the residue thus obtained was diluted with 500 ml. of water. The aqueous solution was extracted four times with 250-ml. portions of ether, and the ether extracts were combined, dried with anhydrous magnesium sulfate, and filtered. On addition of ethereal hydrogen chloride to the ether solution an oily precipitate formed. The ether was decanted, and the precipitate was dissolved in ml. of water, rendered alkaline with sodium hydroxide, and the basic solution was extracted, as before, with ether. The ether extracts were combined, dried with anhydrous magnesium sulfate, filtered, and the ether was evaporated. The viscous oil thus obtained was dissolved in ethyl acetate, diluted with technical hexane and refrigerated. When the base did not separate as a solid, the solution was warmed to about 25 C., and ethereal hydrogen chloride and more anhydrous ether were added. The N-oxide of 4-pyridyl phenyl ketone O-n-propyloxime hydrochloride separated as an oil. The solvent was decanted, water was added, and the solution was rendered alkaline with sodium hydroxide. After extracting the basic aqueous solution with several portions of ether, drying the ether extracts, and evaporating the ether, there was obtained the N-oxide of 4-pyridyl phenyl ketone O-npropyloxime as a yellow viscous oil.

Analysia -Calcd for C H N O C, 70.29; H, 6.29; N, 10.93. Found: C, 69.62; H, 6.46; N, 10.60.

Example 4.-Preparation of the N-oxz'de of 6-methyl-2- pyridyl methyl ketone O-ethyloxime Following the procedure of Example 1, but substituting 6-methyl-2-pyridyl methyl ketoxime for 4-pyridyl methyl ketoxime and substituting ethyl bromide for n-propyl bromide, there was prepared the corresponding N-oxide of 6-methyl-2-pyridyl methyl ketone O-ethyloxime.

Example 5.Preparation 0 the N-Oxide of 5-methyl-2- pyridyl methyl ketone O-benzyloxl'me Following the procedure of Example 1, but substituting S-methyI-Z-pyridyl methyl ketoxime for 4-pyridyl methyl ketoxime and substituting benzyl chloride for n-propyl bromide, there was prepared the corresponding N-oxide of S-methyl-Z-pyridyl methyl ketone O-benzyloxime.

Example 6.Preparati0n of the N-oxide of 4,6-dimethyl- Z-pyridyl methyl ketone O-allyloxime 7 Example 7 .Preparation of the N-oxide of Z-pyrz'dyl isopropyl ketone O-n-amyloxime Following the procedure of Example 1, but substituting Z-pyridyl isopropyl ketoxime for 4-pyridyl methyl ketoxime and substituting n-amyl bromide for n-propyl bromide, there was prepared the corresponding N-oxide of 2-pyridy1 isopropyl ketone O-n-amyloxime.

Example 8.Preparatin of the N-oxide 07 2-pyrt'dyl tert.butyl ketone O-n-hexyloxime Following the procedure of Example 1, but substituting 2-pyridyl tert.butyl ketoxime for 4-pyridyl methyl ketoxime and substituting n-hexyl bromide for n-propyl bromide, there was prepared the corresponding N-oxide of 2-pyridyl tert.buty1 ketone O-n-hexyloxime.

Example 9.Preparati0n of the N-oxide of Z-pyriclyl n-hexyl ketone O-n-octyloxime Following the procedure of Example 1, but substituting 2-pyridyl n-hexyl ketoxime for 4-pyridyl methyl ketoxime and substituting n-octyl bromide for n-propyl bromide, there was prepared the corresponding N-oxide of 2-pyridyl n-hexyl ketone O-n-octyloxime. I

Example J0.Preparation of the N-oxide of 4,5-diethyl- Z-pyridyl n-propyl ketone O-isOpropyloxime Following the procedure of Example 1, but substituting 4,5-diethyl-2-pyridyl n-propyl ketoxime for 4-pyridyl methyl ketoxime and substituting isopropyl bromide for n-propyl bromide, there was prepared the corresponding N-oxide of 4,5-diethyl-2-pyridyl n-propyl ketone O-isopropyloxime.

Example ]1.--Preparati0n of the N-oxide of 5-n-butyl-2- pyridyl n-propyl ketone O-isobutyloxime Following the procedure of Example 1, but substituting S-n-butyl-Z-pyridyl n-propyl ketoxime for 4-pyridy1 methylketoxime and substituting isobutyl bromide for n-pro pyl bromide, there was prepared the corresponding N-oxide of 5-n-butyl-2-pyridyl n-propyl ketone O-isobutyloxime.

Example l2.--Preparati0n of the N-oxz'de of S-pyridyl ethyl ketone O-benzyloxime Following the procedure of Example 1, but substituting 3-pyridyl ethyl ketoxime for 4-pyridyl methyl ketoxime and substituting benzyl chloride for n-propyl bromide, ther was prepared the corresponding N-oxide of 3-pyridyl ethyl ketone O-benzyloxime.

Example 13.Preparati0n 0f the N-oxide of 2,4,6-trimethyl-3-pyridyl methyl ketone O-cyclohexyloxime Following the procedure of Example 1, but substituting 2,4,6-trimethyl-3-pyridy1 methyl ketoxime for 4- pyridyl methyl ketoxime and substituting eyclohexyl bromide for n-propyl bromide, there was prepared the corresponding N-oxide of 2,4,6-trirnethyl-3-pyridyl methyl ketone O-cyclohexyloxime.

Example 14.Preparation of the N-oxide of 6-n-amyl-3- pyridyl n-amyl ketone O-isoamyloxime Following the procedure of Example 1, but substituting 6-n-amyl-3-pyridyl n-amyl ketoxime for 4-pyridyl methyl ketoxime and substituting isoarnyl bromide for npropyl bromide, there was prepared the corresponding N-oxide of 6-n-amyl-3-pyridyl n-amyl ketone O-isoamyloxime.

v 8 Example 16.Preparati0n of the N-oxide 0f Z-methyl-S- ethyl-4-pyrz'tlyl methyl ketone O-(6-0ctenyl)0xime Following the procedure of Example 1, but substituting 2rnethyl-5-ethyl-4-pyridy1 methyl ketoxime for 4- pyridyl methyl ketoxime and substituting 6-octenyl bromide for n-propyl bromide, there was prepared the corresponding N-oxide of Z-methyl-S-ethyl-4-pyridyl methyl ketone G-(S-octenyDoxime.

Example 17.Preparati0tt of the N-oxide 0 2-methyl-4- pyritlyl :z-propyl ketone O-n-tlodecyloxime Following the procedure of Example 1, but substituting Z-methyll-pyridyl n-propyl ketoxime for 4-pyridyl methyl ketoxime and substituting n-dodecyl bromide for npropyl bromide, there was prepared the corresponding N- oxide of 2-methyl-4-pyridyl n-propyl ketone O-n-dodecyloxime.

Example 18.Preparati0n of the N-oxide of 2-methyl-4- pyrz'dyl n-butyl ketone 0-(2-phenethyl)0xime Following the procedure of Example 1, but substituting 2-methyl-4-pyridyl n-butyl ketoxime for 4-pyridyl methyl ketoxime and substituting Z-phenethyl bromide for n-propyl bromide, there was prepared the corresponding N- oxide of 2-methyl-4-pyridyl n-butyl ketone O-(2-phen ethyl) oxime.

Example 19.-Preparatz'0n of the N-oxide of 4-pyridyl ethyl ketone O-(3-phenylpr0p3 l)oxime Following the procedure of Example 1, but substituting 4-pyridyl ethyl ketoxime for 4-pyridyl methyl ketoxime and substituting 3-phenylpropyl bromide tor n-propyl bromide, there was prepared the corresponding N-oxide of 4-pyridyl ethyl ketone O-(3-phenylpropyl)oxirne.

Example 20.Preparati0n of the N-oxide of 2,6-dimethyl-4-pyridyl phenyl ketone 0-(2-cycl0hexenyl)0xime Following the procedure of Example 1, but substituting 2,6-dimethyl-4-pyridyl phenyl ketoxime for 4-pyridyl methyl ketoxime and substituting 2-cyclohexenyl bromide for n-propyl bromide, there was prepared the corresponding N-oxideof 2,6-dimethyl-4-pyridyl phenyl ketone O-(Z- cyclohexenyl) oxime.

Example 21.Preparati0n of the N-oxide of 4-pyridyl pher zyl ketone O-cinnamyloxime Following the procedure of Example 1, but substituting 4-pyridyl phenyl ketoxime for 4-pyridyl methyl ketoxime and substituting cinnamyl bromide for n-propyl bromide, there was prepared the corresponding N-oxide of 4 pyridyl phenyl ketone O-cinnamyloxime.

Example 22.Preparation of the N-oxide of 2-methyl-3- pyridyl phenyl ketone O-crotyloxime Following the procedure of Example 1, but substituting 2-methyl-3-pyridyl phenyl ketoxime for 4-pyridyl methyl ketoxime and substituting crotyl bromide for n-propyl bromide, there was prepared the corresponding N-oxide of 2- n1ethyl-3-pyridy1 phenyl ketone O-crotyloxime.

Example 23.Preparation of the N-oxide 0f 3-pyridyl mtolyl ketone O-(1-methylallyl)0xime Following the procedure of Example 1, but substituting 3-pyridyl m-tolyl ketoxime for 4-pyridyl methyl ketoxime and substituting l-methylallyl bromide-for n-propyl bromide, there was prepared the corresponding N-oxide of 3- pyridyl rn-tolyl ketone 0-(1-methylallyl)oxime.

Example 24.Preparati0n of the N-oxia'e of 3-pyrz'dyl ptolyl ketone O-methallyloxime Following the procedure of Example 1, but substituting 3-pyridyl p-tolyl ketoxime for 4-pyridyl methyl ketoxime and substituting methallyl bromide for n-propyl bromide, there was prepared the corresponding N-oxide of'3-pyridyl p-tolyl ketone O-methallyloxime.

Example 25.Preparation f the N-oxide 0f 3-pyridyl mesityl ketone O-n-propyloxime Following the procedure of Example 3, but substituting the N-oxide of 3-pyridyl mesityl ketone for the N- oxide of 4-pyridyl phenyl ketone, there was prepared the corresponding N-oxide of 3-pyridyl mesityl ketone O-npropyloxime.

Example 26.Preparati0n 0 the N-oxide of Z-pyridyl phenyl ketone O-(Z-cyclopentenylmethyl)oxime Following the procedure of Example 1, but substituting Z-pyridyl phenyl ketoxime for 4-pyridyl methyl ketoxime and substituting Z-cyclopentenylmethyl bromide for npropyl bromide, there was prepared the corresponding N- oxide of Z-pyridyl phenyl ketone O-(2-cyclopentenylmethyl)oxime.

Example 27.--Preparati0n of the N-oxide of 4-methyl-2- pyridyl phenyl ketone O-propargyloxime Following the procedure of Example 1, but substituting 4-methyl-2-pyridyl phenyl ketoxime for 4-pyridyl methyl ketoxime and substituting propargyl bromide for n-propyl bromide, there was prepared the corresponding N-oxide of 4-methyl-2-pyridyl phenyl ketone O-propargyloxime.

Example 28.Preparation of the N-oxide of 2-pyridyl 0- tolyl ketone O-cyclohexylmethyloxime Following the procedure of Example 1, but substituting Z-pyridyl o-tolyl ketoxime for 4-pyridyl methyl ketoxime and substituting cyclohexylmethyl bromide for n-propyl bromide, there was prepared the corresponding N-oxide of Z-pyridyl o-tolyl ketone O-cyclohexylmethyloxime.

Example 29.Preparati0n 0f the N-oxiale 0f Z-isobatyl- 5isopropyl-3-pyridyl methyl ketone O-methyloxime Following the procedure of Example 2, but substituting the N-oxide of 2-isobutyl-5-isopropyl-3-pyridyl methyl ketone for the N-oxide of 4-pyridyl methyl ketone, there was prepared the corresponding N-oxide of 2-isobutyl-5-isopropyl-3-pyridyl methyl ketone O-methyloxime.

Example 30 Ten thousand (10,000) scored tablets for oral use,

each containing 200 mg. of the N-oxide of 4-pyridyl phenyl ketone O-n-propyloxime, are prepared from the following ingredients:

N-oxide of 4-pyridyl phenyl ketone O-n-propyloxime Starch, U.S.P. 170 Ta1c,U.S.P 130 Lactose, U.S.P 2600 Sucrose powder, U.S.P. 37 Calcium stearate 19.5

The finely powdered lactose and sucrose are mixed well and the mixture is granulated with starch paste. The wet mass is forced through an S-mesh screen, dried at 120 F. in a force-air oven, and then put through a 16-mesh screen. The remainder of the ingredients, in fine powder form, are mixed well and then mixed with the dried lactose granules. The final mixture is then compressed into tablets.

Example 31 Ten thousand (10,000) two-piece hard gelatin capsules for oral use, each containing 100 mg. of the N-oxide of 4-pyridyl methyl ketone O-n-propyloxime, are prepared from the following ingredients:

N-oxide of 4-pyridyl methyl ketone O-n-propyloxime 1000 Lactose, U.S.P 750 Starch, U.S.P 300 Talc, U.S.P. 65 Calcium stearate 25 10 One to two capsules are administered every 4 hours for controlling epilepsy and psychomotor seizures.

Example 32 One-piece soft elastic capsules for oral use, each containing 25 mg. of the N-oxide of 4-pyridyl methyl ketone O-n-propyloxime, are prepared in the usual manner by first dispersing the powdered active material in sufficient corn oil to render the material capsulatable.

One to two capsules are administered 4 times daily to relieve pain and stiffness in muscles and joints.

Example 33 An aqueous preparation for oral use containing 350 mg. of the N-oxide of 4-pyridyl methyl ketone O-n-propyloxime in each 5 ml. is prepared from the following ingredients N-oxide of 4-pyridyl methyl ketone O-n-propyloxime g 700 Methylparaben, U.S.P. g 7.5 Propylparaben, U.S.P. g 2.5 Saccharin sodium g 12.5 Cyclamate sodium g 2.5 Glycerin ml 3000 Tragacanth powder g 10 Orange oil flavor g 10 ED. and C. orange dye g 7.5

Deionized water, q.s. to 10,000 ml.

One teaspoonful is administered 3 times daily to control emotional disturbances such as anxiety, tension, tension headache, agitated depression, and acute agitation.

Example 34 One to two ml. is injected for the relief of pain and the acute phase of skeletal muscle spasm.

Example 35 Ten thousand (10,000) two-piece hard gelatin capsules for oral use, each containing 50 mg. of the N-oxide of 4- pyridyl methyl ketone O-n-propyloxime and 65 mg. of ethoxazolamide, are prepared from the following ingredients:

N-oxide of 4-pyridyl methyl ketone O-n-propyloxime 500 Ethoxazolarnide 650 Corn starch, U.S.P. 500 Magnesium stearate 25 Talc, U.S.P. 65

One to two capsules are administered 3 times daily for the relief of premenstrual tension.

Example 36 Ten thousand (10,000) tablets for oral use, each containing 75 mg. of the N-oxide of 4-pyridyl methyl ketone O-n-propyloxime, 1 mg. of methylprednisolone, and 300 mg. of aspirin, are prepared from the following ingredients:

N-oxide of 4-pyridyl methyl ketone O-n-propyloxime 750 Methylprednisolone 10 Aspirin 3000 Starch 750 Magnesium stearate 25 Talc 50 The ingredients are mixed carefully and slugged. The slugs are broken into granules which are compressed into tablets of the correct weight.

The tablets so prepared are useful in the treatment of moderate cases of rheumatoid arthritis by the administration of 1 to 2 tablets 3 to 4 times daily.

I claim:

1. An N-oxide of 4-pyridyl phenyl ketone O-alkyloxime wherein alkyl is of from 1 to 12 carbon atoms, inclusive.

2. The N-oxide of 4-pyridy1 phenyl ketone O-n-propyl- 1O oXime.

References Cited by the Examiner UNITED STATES PATENTS 2,785,170 3/57 Kagan.

12 2,785,171 3/57 Birkenmeyer. 2,816,113 12/57 Wilson et a1. 2,924,604 2/60 Steinhards et a1. 260296 3,060,177 10/62 Druey et a1.

OTHER REFERENCES Chemical Abstracts, vol. 51, p. 14721 (1957), abstracting Eckstein et al., Dissertations Pharrn., vol 8, pp. 239- 47 (1956).

Chemical Abstracts, vol. 52, pp. 63378 (1958), abstracting Eckstein et al., Dissertations Pharm., vol 9, pp. 197204 (1957).

.Culvenor: Rev. of Pure and Applied Chemistry, vol. 3, No. 2, pages 83-114 (1953).

5 WALTER A. MODANCE, Primary Examiner.

DUVAL T. MCCUTCHEN, IRVING MARCUS,

Examiners. 

1. AN N-OXIDE OF 4-PYRIDYL PHENYL KETONE O-ALKYLOXIME WHEREIN ALKYL IS OF FROM 1 TO 12 CARBON ATOMS, INCLUSIVE. 